Development of gene therapy product for treating MPS IIIB

项目摘要 NeuroGT，Inc是一家由基因治疗副教授傅海燕博士创立的新兴公司 中心位于查佩尔山的北卡罗来纳州大学，其使命是开发和商业化有效的 基因治疗产品来治疗人类罕见的神经遗传性疾病。 本项目的目标是开发一种有效的基因治疗产品， 人类粘多糖样变性（MPS）IIIB。MPS IIIB是一种致死性溶酶体贮积病（LSD），由 α-N-乙酰氨基葡萄糖苷酶（NAGLU）的常染色体隐性缺陷，导致严重的神经系统疾病 症状、广泛的躯体疾病和过早死亡。MPS IIIB尚无有效治疗方法。 针对根本原因的基因治疗已被证明是治疗单基因 包括迷幻药在内的疾病。我们之前的研究已导致IND批准用于1/2期GT临床试验， MPS IIIA（NCT 02716246）、MPS IIIB（NCT 03315182）和MPS II（IND# 17838）患者，使用反式 通过全身递送的BBB-亲神经性AAV 9载体。 为了提高治疗潜力，我们开发了三种新的第二代（2nd-gen）基因疗法 MPS IIIB的产品，使用AAV 9平台递送密码子优化的人NAGLU基因（hNAGLUop） 由不同的推动者推动。密码子优化导致增强的rNAGLU分泌，表明 潜在的旁观者效应。我们已经在小鼠中测试了第二代rAAV 9-hNAGLUop载体之一， IV注射，并显示载体治疗对治疗MPS IIIB安全有效，支持 进一步发展为人类临床应用的潜力。在这个项目中，与 考虑到人类翻译和商业化，我们将扩大我们的努力，以测试的有效性和安全性， 这些rAAV 9-hNAGLUop产物通过全身递送在小鼠中产生严格的临床前数据，以支持 IND提交和临床开发。

Project Summary NeuroGT, Inc is a new start-up company founded by Dr. Haiyan Fu, Associate professor in the Gene Therapy Center at University of North Carolina at Chapel Hill, with the mission of develop and commercialize effective gene therapy products to treat rare neurogenetic diseases in humans. The goal of this project is to develop an effective gene therapy product targeting the root cause for treating Mucopolysaccharidosis (MPS) IIIB in humans. MPS IIIB is a fatal lysosomal storage disease (LSD) caused by autosomal recessive defects in α-N-acetylglucosaminidase (NAGLU), leading to severe neurological manifestations, broad somatic disorders and premature death. No effective treatment is available for MPS IIIB. Gene therapy targeting the root cause has been demonstrated to be an ideal strategy for treating monogenic diseases including LSDs. Our previous studies have led to IND approvals for Phase 1/2 GT clinical trials in patients with MPS IIIA (NCT02716246), MPS IIIB (NCT03315182), and MPS II (IND# 17838), using the trans- BBB-neurotropic AAV9 vector via a systemic delivery. For improved therapeutic potential, we have developed three new 2nd-generation (2nd-gen) gene therapy products for MPS IIIB, using the AAV9 platform to deliver a codon-optimized human NAGLU gene (hNAGLUop) driven by different promoters. The codon-optimization resulted in enhanced rNAGLU secretion, indicating the potential of added by-stander effects. We have tested one of the 2nd-gen rAAV9-hNAGLUop vector in mice via an IV injection, and shown that the vector treatment was safe and effective for treating MPS IIIB, supporting the potential of further development towards clinical application in humans. In this proposed project, with human translation and commercialization in mind, we will expand our efforts to test the efficacy and safety of these rAAV9-hNAGLUop products in mice via systemic delivery to generate rigorous preclinical data to support the IND submission and clinical development.